Tofacitinib citrate chemically known as 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile, 2-hydroxypropane-1,2,3-tricarboxylate described below in figure 1 and as disclosed in the WO 02/096909 and U.S. Pat. No. 7,301,023, was approved in November 2012 by US FDA with the trade name as Xeljanz, a film coated tablet, for rheumatoid arthritis. Other indications are described in US2004/0053947. Tofacitinib and its corresponding citrate salt are useful as inhibitors of protein kinases such as the enzyme Janus Kinase 3 also referred as JAK 3. Tofacitinib Citrate is extremely bitter in taste.

Rheumatoid Arthritis (RA) is one of the common forms of autoimmune disease. RA is a chronic systemic disease affecting the joints, muscle, tendons, connective tissues and fibrous tissue. Pain, swelling, and redness are common joint indications. RA affects over 21 million people worldwide. RA can start at any age, but the peak age of onset is between 30 and 55 years. Twice as many women are generally affected by RA than men, and the disease also impacts on the average life expectancy, shortening it by three to seven years. After 10 years, less than 50% of patients with RA can work or function normally on a day-to-day basis.
IP.com article titled “Tasocitinib Oral Tablet Composition” numbered IPCOM000202830D, dated 4 Jan. 2011, disclosed Tasocitinib immediate release oral tablets. The tablet compositions disclosed in the said article are Tofacitinib oral film coated tablet compositions with dry granulation manufacturing process. US 2012/0195933A1, describes Tasocitinib i.e. Tofacitinib composition and process to prepare the same, but is silent about ODT compositions.
USRE41783 which is basic molecule patent of Tofacitinib describes that pharmaceutical compositions may take the form of, tablets or capsules prepared by conventional means. It then describes compositions comprising binding agents etc. It does not provide any specific motivation to produce tablets without binding agents.
U.S. Pat. No. 6,956,041 and U.S. Pat. No. 7,265,221 disclose in generalized language the invention i.e. Tofacitinib may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers without providing any motivation to produce orally dispersible tablet composition. These are silent about taste of Tofacitinib. Tofacitinib is extremely bitter in taste.
Possibly its extreme bitter taste has resulted into film coated compositions.
Prior art is silent about orally dispersible tablet composition or the process to prepare it.
U.S. Pat. No. 7,301,023 reports one of the polymorphic forms of Tofacitinib. Possibility of active ingredient exhibiting polymorphs creates stability issues in the composition acceptability. Their stability is unpredictable. Heating during granulation and moisture contact during wet granulation or compaction process many times lead to changes in physicochemical properties of active ingredient. Changes in molecular structures and molecular arrangements result into polymorphic change. These changes impact the performance of the formulation negatively. Stability of active or its polymorphic form is of critical importance. It is necessary for the formulation to retain the form that was incorporated.
Tofacitinib compositions as available in the prior art when tried for preparation of ODT, ODT cannot be prepared. Several processing problems were experienced. Tablets produced did not conform to the criteria of orally dispersible tablets. It was also observed that Tofacitinib when tried to formulate into tablet, leads to sticking problems. Such problems were also experienced when conventional means were tried to prepare the tablets.
Conventional formulations have several disadvantages and inability to promote the patient compliance is one of the main disadvantages. Conventional compositions are not patient friendly. Disadvantage of conventional formulation is that it has to be swallowed with water. Difficulties in taking pills or tablets with water are known. As a result, aged persons, children and the people on the move often experience difficulty in complying. RA patients are normally found in the age group above 35. As age increases, the gravity tends to increase. In older age population, patient compliance is a known problem. Conventional compositions further deteriorate the compliance. Existing composition of Tofacitinib are not fit to be consumed as orally dispersible or chewable compositions as Tofacitinib is extremely bitter.
Albeit Tofacitinib is bitter in taste, there is a need to provide a patient friendly composition of Tofacitinib. There is a need for Tofacitinib composition which can be taken without the rigors and hardships of swallowing it with water.
Tofacitinib crumbles and disintegrates and these undesirable properties make it difficult to formulate into dispersible tablet.
The bitter taste of Tofacitinib poses a great challenge for the development of orally disintegrating tablets (ODTs) formulation. Besides bitter taste, developing ODT is not simple.
Not every active pharmaceutical ingredient can be formulated into ODT. There are several limitations, like, stability of active, its processability, its ability to go into solution from tablet, its ability to support a defect free tablet formation and of all ability to combine with sweetener to mask the unpleasant or bitter taste and yet produce a stable orally disintegrating composition. Sometimes although sweeteners are added, there is unpleasant bitter after taste. These are just some of the limitations. Similarly there may be several other limitations which are active ingredient specific and can't be guessed or foreseen. Therefore, formulating an ODT is a challenge. Normally if the tablet weight is reduced several processing problems are faced for example, poor blend flow, tablet picking, sticking and all other compressibility issues. Therefore producing orally disintegrating tablets with reduced weight is a further challenge.
Orally disintegrating tablets (ODTs) have gained considerable attention as a preferred alternative to conventional tablets and capsules due to better patient compliance especially for the pediatric, geriatric, psychiatric patients and patients with nausea, vomiting and motion sickness complications. ODTs are solid dosage forms containing medicinal substances which disintegrate rapidly, usually within a matter of seconds, when placed upon the tongue. Orally disintegrating tablets are appreciated by a significant segment of populations particularly who have difficulty in swallowing. ODTs with good taste and flavor increase the acceptability of bitter drugs by various groups of population.
Orally disintegrating tablets (ODTs) disintegrate or dissolve in the mouth rapidly. Resulting liquid in the mouth can be swallowed easily. No additional water is required to be administered. This special property of ODT provides the convenience of a tablet formulation, ease of handling yet provides the ease of swallowing provided by a liquid formulation. Besides ease of administration ODTs give pleasant mouth feel. ODTs encourage patients to adhere to medication, especially the elderly patients and children who have difficulty in swallowing conventional tablets. ODTs ensure accurate dosing better than oral liquids. Ease of swallowing the tablet that is liquefied in the mouth is of immense importance when water is not available to swallow the tablet as well as in specific conditions or when the patient is not in a condition to use water and swallow the conventional tablet.
Hence, there is a need of a patient's friendly Tofacitinib Citrate ODT formulation. There is a need of a process to produce a Tofacitinib Citrate ODT formulation avoiding drawbacks of processes used to produce conventional tablets. Present invention discloses some such processes and ODT compositions. Invention also describes direct compression manufacturing process. Secondly, there is a pressing need to have a Tofacitinib composition which is in the form of smaller tablet yet orally dispersible. ODT of the present invention rapidly disintegrates in the buccal cavity, dispersing the contents and has a pleasant taste with smooth creamy mouthfeel. It can be taken without water, so it ensures better patient compliance.